Biodegradeable putty compositions and implant devices, methods, and kits relating to the same

ABSTRACT

Disclosed are phospholipid based compositions and implant devices, as well as methods and kits that include such compositions or components thereof. In particular, the present compositions include a polymer component such as a poloxamer or PEG component and a phospholipid component, such as a Phosal. The present compositions may include at least one additional component, such as granules, powder and/or particulates. The present compositions may further include one or more bone graft materials and/or active ingredients. The compositions may be used on their own or incorporated on or in a surgical implant.

CROSS REFERENCE TO RELATED APPLICATION

This patent application is a continuation of U.S. patent applicationSer. No. 14/218,509, filed Mar. 18, 2014, now U.S. Pat. No. 9,498,558,which is a divisional of U.S. patent application Ser. No. 13/246,999filed Sep. 28, 2011, now U.S. Pat. No. 8,716,363, which are herebyincorporated by reference in their entireties for all purposes.

FIELD

The present invention generally relates to carrier compositions whichmay be used to carry e.g., bone graft materials and/or for drug deliveryto a mammal. Example carrier compositions include phospholipid-basedcarriers that may be prepared e.g., in the form of a putty or paste. Theinvention also generally relates to implant devices and methods ofmaking and using the present compositions, as well as kits that includesuch compositions or components thereof.

BACKGROUND

First generation synthetic bone graft substitutes were in the form ofloose particles, beads, etc. Examples includes Vitoss bone void filler,ActiFuse granules etc. The intraoperative handling of these products haspresented a challenge during surgery, however.

SUMMARY

The present inventor has developed novel phospholipid-based carrierswhich may be useful, e.g., to carry and improve the handlingcharacteristics of granules, such as MicroFuse® Granules (GlobusMedical, Inc.), or for carrying powders or particulates. Examplephospholipid-based carrier compositions include at least one a polymercomponent (such as Pluronic/Poloxamer or Polyethylene Glycol (PEG),e.g., Pluronic F127 also known as Poloxamer 407) and at least onesoybean derived lipid/phospholipid component (such as Phosal 50PG).Thus, example embodiments herein are generally related to compositionsthat include a phospholipid-based carrier that includes at least onepolymer (e.g. poloxamer or PEG) component and at least one phospholipid(e.g., Phosal) component. According to non-limiting example embodiments,the present compositions may further include granules, powder and/orparticulates. According to non-limiting example embodiments, the presentcompositions may be in the form of a putty or paste. Alternatively, thecarrier may be in the form of a dough-like carrier or have a paste-likeconsistency, which forms may become more putty-like or flowable whencombined with granules, powder and/or particulates. Example embodimentsof compositions herein may further include one or more graft materials(such as synthetic BGS) and/or one or more active ingredients.

Other example embodiments include, one or more implant devices that mayinclude a device for placement into a mammal, such as a human, and oneor more of the present compositions thereon or therein. The compositionsin these embodiments may additionally include any component known tothose skilled in the art that may be desirable for implantation with thedevice, such as one or more bone graft materials and/or activeingredients.

Further provided are methods of making compositions for implantationinto a mammal. In the present methods, one may start out with granules(e.g., MicroFuse Granules), powder or particulates; or with aphospholipid-based carrier composition (e.g., MicroFuse Putty) that maycontain one or more of granules, powder and particulates; and add bloodor bone marrow aspirate (BMA) thereto. The methods may further includemixing the present compositions with at least one component selectedfrom the group consisting of one or more graft materials and one or moreactive ingredients.

Also provided are methods of treating mammals by administering to amammal at least one of the present compositions. Such methods mayfurther include administering one or more graft materials and/or one ormore active ingredients, either as part of the present compositions oralong therewith.

According to non-limiting example embodiments, the present compositionsmay be administered directly to a mammal, or alternatively in or on animplant that is inserted into a mammal, e.g., during a surgicalprocedure.

Other example embodiments are directed to kits that include the presentcompositions or one or more ingredients thereof (such as a polymer and aphospholipid component), and may further include e.g., instructions formaking and/or using the compositions; one or more implant devices intoor onto which the composition may be incorporated; tools or devices formixing and/or storing the compositions; tools or devices for insertingthe present compositions or implant devices into a mammal; one or moregranules, powder or particulates to be added to the composition; one ormore graft materials and/or active ingredients that may be provided withor carried by the present compositions; and/or any other components ordevices that may be useful in making and/or using the presentcompositions or implant devices.

The foregoing has outlined rather broadly the features and technicaladvantages of the present invention in order that the detaileddescription of the invention that follows may be better understood.Additional features and advantages of the invention will be describedherein, which form the subject of the claims of the invention. It shouldbe appreciated by those skilled in the art that any conception andspecific embodiment disclosed herein may be readily utilized as a basisfor modifying or designing other structures for carrying out the samepurposes of the present invention. It should also be realized by thoseskilled in the art that such equivalent constructions do not depart fromthe spirit and scope of the invention as set forth in the appendedclaims. The novel features which are believed to be characteristic ofthe invention, both as to its organization and method of operation,together with further objects and advantages will be better understoodfrom the following description when considered in connection with theaccompanying figures. It is to be expressly understood, however, thatany description, figure, example, etc. is provided for the purpose ofillustration and description only and is by no means intended to definethe limits the invention.

BRIEF DESCRIPTION OF THE FIGURES

Non-limiting example embodiments described herein, with reference to thefollowing accompanying Figures.

FIG. 1 depicts a syringe having therein synthetic bone graft substitutepolymer granules by Globus Medical, Inc., under the trade nameMicroFuse® Granules, which may be added e.g., to the present carriercompositions;

FIG. 2 depicts a non-limiting example of a phospholipid-based carrier ofthe present invention, which in the depicted embodiment includesPluronic F127 and Phosal 50 PG. In the depicted embodiment, the carrieris a bioresorbable carrier in the form of a putty, which has been shapedinto a ball. It should be understood, however, that the carrier can beshaped into any desirable shape;

FIG. 3 depicts a non-limiting example of a composition of the presentinvention, which includes e.g., biodegradable polymer granules, such asthe MicroFuse® Granules depicted in FIG. 1, which have been combinedwith a bioresorbable phospholipid-based carrier, which includes PluronicF127 and Phosal 50 PG, as depicted in FIG. 2, to form novel compositionsaccording to example embodiments of the present invention;

FIG. 4 depicts a method of combining bone marrow aspirate (BMA) withgranules, such as MicroFuse® Granules, e.g., using a luer lock syringe;

FIG. 5 depicts a composition according to the present invention, such asthe composition depicted in FIG. 3, before (on the left) and after (onthe right) being mixed with BMA;

FIG. 6 depicts Pluronic F127 and Phosal 50 PG, which are non-limitingexamples of polymers and phospholipids that may be used in accordancewith the present invention; and

FIG. 7 is a flow chart setting forth an example method of preparing acomposition according to the present invention.

DETAILED DESCRIPTION

The aspects, advantages and/or other features of example embodiments ofthe invention will become apparent in view of the following detaileddescription, taken in conjunction with the accompanying drawings. Indescribing example embodiments, specific terminology is employed for thesake of clarity. However, the embodiments are not intended to be limitedto this specific terminology. It should be apparent to those skilled inthe art that the described embodiments of the present invention providedherein are merely exemplary and illustrative and not limiting. Numerousembodiments of modifications thereof are contemplated as falling withinthe scope of the present invention and equivalents thereto. It is to beunderstood that each specific element includes all technical equivalentsthat operate in a similar manner to accomplish a similar purpose.

Unless otherwise noted, technical terms are used according toconventional usage. Any patents and/or publications mentioned in thisspecification are indicative of the level of those skilled in the art towhich the invention pertains. All publications, patent applications,patents, and other references mentioned herein are incorporated byreference in their entirety.

Amounts and other numerical data may be presented herein in a rangeformat. It is to be understood that such range format is used merely forconvenience and brevity and should be interpreted flexibly to includenot only the numerical values explicitly recited as the limits of therange, but also to include all the individual numerical values orsub-ranges encompassed within that range as if each numerical value andsub-range is explicitly recited.

As used herein, “a” or “an” may mean one or more. As used herein,“another” may mean at least a second or more. Furthermore, unlessotherwise required by context, singular terms include pluralities andplural terms include the singular.

The terms “drug” and “active ingredient” are used herein to include anydrug or other active ingredient that may be added to the presentcompositions for treating mammals, such as humans, for a variety ofdifferent conditions.

The terms “granule”, “particle,” “particulate,” “sphere,” and“microsphere” are used somewhat interchangeably herein and are intendedto encompass granules that are essentially discrete from one another.The term “granule” may include e.g., multiple “spheres”, “microspheres”or other particles that may be bonded together, for example, by heatingto obtain granules. The terms may include various particles, granules,chips, beads, etc., regardless of shape. Accordingly, the terms“granule”, “particle,” “particulate,” “sphere” and “microsphere” and thelike are intended to be very broad and encompass many shapes, includingspheres, spheroids, rods, pellets, granules, blocks, grains or any othersuitable shape.

A “resorbable” or “biodegradable” material may include for exampleceramics, polymers or other materials that are designed to be resorbedby the body of a mammal, and eventually replaced with healthy tissue.The terms “degradation rate,” “degradation profile,” “resorption rate,”and “resorption profile” are all used somewhat interchangeably hereinand are intended to refer to the time over which a resorbable materialis resorbed by the body. Degradation or resorption rates may varysomewhat depending on various factors such as material selection,placement location in the body, temperature, surrounding tissue, etc.

As used herein, “biocompatible” means the ability of an object to beaccepted by and to function in a mammal without eliciting a significantforeign body response (such as, for example, an immune, inflammatory,thrombogenic, or like response).

As used herein, “polymer” means a chemical compound or mixture ofcompounds formed by polymerization and including repeating structuralunits. Polymers may be constructed in multiple forms and compositions orcombinations of compositions. The term “polymer” is also intended tocover copolymer materials and polymer blends formed from two or morepolymers. Examples of suitable polymers that may be used include, butare not limited to, biocompatible and/or bioabsorbable polymers orcopolymers and combinations thereof. Non-limiting examples include,poly(hydroxy acids), poly(phosphazenes), poly(amino acid-carbonates),poly(anhydrides), and poly(urethanes).

One of ordinary skill in the art will appreciate that the selection of asuitable polymer depends on several factors. For example, factors in theselection of the appropriate polymer(s) that is used may includebioabsorption (or bio-degradation) kinetics; in vivo mechanicalperformance; cell response to the material in terms of cell attachment,proliferation, migration and differentiation; and biocompatibility.Other relevant factors, which to some extent dictate the in vitro and invivo behavior of the polymer, include the chemical composition, spatialdistribution of the constituents, the molecular weight of the polymer,and the degree of crystallinity. The selection of polymer materialshaving varying resorption profiles would allow a multi-phase compositionor implant to degrade in a step-wise manner, thus allowing for gradualtissue in-growth. Standard techniques used in the art such as varyingmolecular weight, copolymer ratio, and crystallinity can be used tofurther differentiate degradation properties of the polymers.

Granules have been used as a synthetic bone graft substitute, howeverthe handling of loose granules with BMA/autograft has presentedchallenges during spinal fusion surgery, e.g., with respect to handlingand containment of the granules at a site during a procedure. To addressthis challenge, the present inventor developed the present compositionse.g. in a putty form in which granules, powders and/or particulates maybe held together by an inert, biocompatible, resorbable carrier.

Compositions

According to non-limiting example embodiments present compositionsinclude a polymer component (such as Pluronic/poloxamer or PEG) and asoybean derived lipid/phospholipid component (such as “Phosal”). By wayof non-limiting example, the polymer component of the carrier mayinclude a poloxamer component (such as Pluronic F127 also known asPoloxamer 407, or other pluronic polymers) or a PEG polymer. Thephospholipid component may be a Phosal component (such as Phosal 50 PG).The present carrier compositions, which include a soybean derived lipidmixed with a polymer having a low melting temperature (e.g., PluronicF127 with a melt point of 60° C.) results in a unique carrier, which maybe used as a carrier to deliver e.g., granules, powder and/orparticulates. Thus, according to non-limiting example embodiments, thepresent compositions may further include one or more of granules, powderand particulates.

Granules: may include for example, MicroFuse granules or granules/beadsmade of e.g., PLGA or PLA or PCL as discussed further below. Powders mayinclude for example, DBM (demineralized bone matrix) powder, or calciumphosphate powder. Particulates may include for example, ceramic/β-TCPparticles such as Vitoss granules or MasterGraft.

According to non-limiting example embodiments, granules may include oneor more of various grades of polymers, including but not limited to PLA,PLGA, PCL, etc. According to example embodiments, the granules may bebiodegradable. Polymer granules may be useful for applications such asdrug delivery, or delivery of growth factors. According to exampleembodiments, the polymer granules include at least two different typesof granules having at least two different compositions. For example, thepolymer granules may include granules having two or more differentdegradation rates. By way of non-limiting example embodiments, the atleast two different types of granules may include for example, two ormore types of PLGA and/or PLA microspheres. By way of further example,the at least two types of granules include 82:18 poly(L-lactide-co-glydolide) and 85:15 poly (D,L lactide-co-glycolide). Itwould be apparent to those skilled in the art that the granules may bevarious grades, including 82:18 PLGA, 85:15 PLGA, 70:30 PLDLA, etc.

According to non-limiting example embodiments, the polymer granules maybe present in approximately equal amounts. For example, 82:18 poly(L-lactide-co-glydolide) and 85:15 poly (D,L lactide-co-glycolide) maybe present in about a 50:50 mix. According to other embodiments, thepolymers may be formed into microspheres and then combined in a range ofabout 95:5 to 5:95 depending on the desired resorption profile. Inexample embodiments, the ratio may be about 80:20-20:80 or 40:60-60:40or 45:55-55:45 of the polymers or any range there-between depending e.g.on a desired resorption profile.

In exemplary embodiments, various forms of the same polymer, poly(lactide-co-glycolide), may be used to give particles with varyingdegradation profiles. The copolymer 82:18 poly (L-lactide-co-glycolide)has been shown to have a degradation time of 6-9 months while 85:15 poly(D,L lactide-co-glycolide) degrades in 2-3 months.

One could make the granules out of microspheres derived from thesePLA/PLGA type polymers. One could also make granules from spheres out oftwo different types of polymers (e.g., 2 PLGAs, 1 PLA-1PLGA, 2 PLAs).

As discussed above, granules may include e.g., microspheres, beads, orother particles of similar or different shapes and sizes. The granulesmay be non-bonded, loose granules. According to non-limiting examples,the granules may include two or more types of PLGA of a granule size ofabout 600-850 micron. But the spheres/granules may be made out of anyPLA/PLGA polymers in whatever size is desired. By way of non-limitingexample, spheres may be made that are less than 125 microns, 125-250microns, 250-500 microns, 600-850 microns, 850 microns and above, or anydesirable size or range of sizes.

To form granules, after the spheres, beads, or other shaped particlesare obtained, they may be thermally sintered or bonded e.g. by heatingto obtain granules.

Granules herein may be for example, MicroFuse® Granules, which are ahighly engineered bone void filler specifically designed with porosityand strength to provide an advantageous environment for regeneratingbone. As indicated above, other granules, powders and/or particulatesmay be used in conjunction with the present phospholipid-based carrierseither as part of the carrier or administered along therewith. By way ofnon-limiting example, granules, powders and particulates that may beused in accordance herewith may include one or more of the following:

a) Ceramic beads/particulates /granules, such as Vitoss granules (madeof β-TCP),

b) Calcium Phosphate particles,

c) Hydroxyapatite particles,

d) Silicated hydroxyapatite particles,

e) Bioactive Glass particles,

f) Cancellous Chips (allograft bone)

g) Cortical bone chips (allograft bone), and/or

h) Demineralized Bone Matrix (DBM) chips or powder,

As indicated above, the present compositions (which may be combined withthe granules, powder and/or particulates) include at least one polymercomponent such as a poloxamer (pluronic) or PEG component, and at leastone phospholipid component.

The polymer component may include for example, one or more poloxamers,such as Pluronic F127 or Poloxamer 407 or other polymers in the familyof poloxamers/pluronics, which includes, but is not limited to Pluronic10R5, Pluronic 17R2, Pluronic 17R4, Pluronic 25R2, Pluronic 25R4,Pluronic 31R1, Pluronic F 108 Cast Solid Surfacta, Pluronic F 108 NF,Pluronic F 108 Pastille, Pluronic F 108 Prill, Pluronic F 108 NF PrillPoloxamer 338, Pluronic F 127, Pluronic F 127 Prill, Pluronic F 127 NF,Pluronic F 127 NF 500 BHT Prill, Pluronic F 127 NF Prill Poloxamer 407,Pluronic F 38, Pluronic F 38 Pastille, Pluronic F 68, Pluronic F 68Pastille, Pluronic F 68 LF Pastille, Pluronic F 68 NF, Pluronic F 68 NFPrill Poloxamer 188, Pluronic F68 Prill, Pluronic F 77, Pluronic F 77Micropastille, Pluronic F 87, Pluronic F 87 NF, Pluronic F 87 NF PrillPoloxamer 237, Pluronic F 87 Prill, Pluronic F 88, Pluronic F 88Pastille, Pluronic F 88 Prill, Pluronic F 98, Pluronic F 98 Prill,Pluronic L 10, Pluronic L 101, Pluronic L 121, Pluronic L 31, Pluronic L35, Pluronic L 43, Pluronic L 44, Pluronic L 61, Pluronic L 62, PluronicL 62 LF, Pluronic L 62D, Pluronic L 64, Pluronic L 81, Pluronic L 92,Pluronic L 44 NF INH surfactant Poloxamer 124, Pluronic N 3, Pluronic P103, Pluronic P 104, Pluronic P 105, Pluronic P 123 surfactant, PluronicP 65, Pluronic P 84, and Pluronic P 85. Pluronic F127 or Poloxamer 407is a hydrophilic non-ionic surfactant of the more general class ofcopolymers known as poloxamers. Poloxamer 407 is a triblock copolymerconsisting of a central hydrophobic block of polypropylene glycolflanked by two hydrophilic blocks of polyethylene glycol. Theapproximate lengths of the two PEG blocks is 101 repeat units while theapproximate length of the propylene glycol block is 56 repeat units. Theparticular compound is also known by the BASF trade name Pluronic F127.As used herein, the term Pluronic F127 is intended to refer to allpoloxamer 407 compounds whether made by BASF or any other maker.

As indicated above, the polymer component may comprise a PolyethyleneGlycol (PEG) component, such as PEG of various grades PEG 1000, PEG1500, PEG 2000, PEG 4000, PEG 8000, PEG 10000, and/or PEG 20000.

The phospholipid, such as Phosal 50 PG is a soybean derived component,and is a standardized phosphatidyl-choline concentrate with at least 50%PC and propylene glycol. Phosal 50 PG is just one member out of a familyof Phosal series that may be used in accordance with the presentinvention, which includes other lipids such as Phosal 53 MCT, Phosal 75SA, Phosal 25 PG, Phosal 35 SB, Phosal 50 SA, etc. Certain phospholipidsmay not be suitable for the present compositions. For example,phospholipons may not be suitable, as they are solid.

According to example embodiments, the phospholipids of the presentcomposition may be pharmaceutical grade.

The present carrier compositions may include for example about 35%-70%by weight of the polymer component (such as Pluronic F127) and about65%-30% by weight of the phospholipid component (such as Phosal 50PG).

According to example embodiments, the present carriers may include forexample about 59%-69% or about 64% by weight of the polymer componentand about 31%-41% or about 36% by weight of the phospholipid component.These amounts may be particularly advantageous for example if granulesare to be added to the carriers in forming the present compositions. Theweight percents of polymer and phospholipid components would bedifferent of course in an overall composition that further includesadditional components such as granules. In this case, for example, thepresent composition may include for example about 33%-43% by weight ofgranules, about 35%-45% by weight of polymer component (such as PluronicF127) and about 18%-27% by weight of phospholipic component (such asPhosal 50 PG). In particular, the composition may include about 38% byweight of biodegradable polymer granules, about 40% by weight of thePluronic F127, and about 22% by weight of the Phosal 50 PG.

According to example embodiments, the present carriers may include forexample about 45%-50% by weight of the polymer component (such asPluronic F127) and about 50%-55% by weight of the phospholipid component(such as Phosal 50PG). These amounts may be particularly advantageousfor example if particulates or powder, such as ceramic particles (Vitossor Mastergraft), bioactive glass, etc., are to be added to the carriersin forming the present compositions.

Thus, non-limiting example compositions that include a polymercomponent, phospholipid component, and at least one third component, mayinclude the following the components (by weight %):

When you use MicroFuse Ceramic Bioactive DBM . . . Granules ParticlesGlass Powder 3^(rd) component 33-43% 45-55% 40-50% 40-50% Polymer (e.g.,35-45% 22-32% 22-32% 22-32% Pluronic F127) Phospholipid 17-27% 17-27%22-32% 22-32% (e.g., Phosal 50PG)

Thus, the final compositions may include for example about 22%-45% ofthe polymer component (e.g., Pluronic F127), about 17-32% of thephospholipid component (e.g., Phosal 50 PG), and about 33-55% of a thirdcomponent (such as granules, powder, particles, etc).

According to non-limiting example embodiments, the present compositionsmay be in the form of a putty. According to non-limiting embodiments,the carrier may be soft, moldable and dough-like, or may have more or apaste like consistency before being combined or mixed with granules,powder or particulates. Such carrier may become more putty-like whencombined with e.g., granules, powder and/or particulates. For example, acarrier composition that includes about 64% Pluronic F127 and about 36%Phosal 50PG would give a dough-like carrier that results in a putty-likeformulation when mixed with MicroFuse Granules. A carrier compositionthat includes about 45-50% Pluronic F127 and about 50-55% Phosal 50PGwould give a carrier with more of a paste like consistency. This is goodfor powdery or particulate materials.

Advantageous features of the present compositions may include one ormore of the following: the phospholipid carrier will allow betterhandling of the granules at an implantation site in a mammal; thephospholipid carrier resorbs quickly in the body (e.g., in less than 5days, or in less than 3 days, i.e., 72 hours) and will leave thegranules behind for bone regeneration (the granules having one or moreslower degradation rates of e.g., 2-3 months and/or 6-9 months), alongwith any other optional graft material and/or active ingredient; and thecarrier is also osteopromotive, or in other words supports boneregeneration.

According to non-limiting example embodiments, the present compositionsmay further include one or more graft materials and/or one or moreactive ingredients. The one or more graft materials may include forexample, synthetic BGS (Bone Graft Substitute). The graft materials mayalso include for example, bone, autogenous graft, blood, BMPs, growthfactors, and/or ceramic particles. By way of example, the presentcompositions may include one or more of the following:

a) Ceramic beads/particulates /granules such as Vitoss granules (made offβ-TCP),

b) Calcium Phosphate particles,

c) Hydroxyapatite particles such as MasterGraft,

d) Silicated hydroxyapatite particles,

e) Bioactive Glass particles,

f) Cancellous Chips (allograft bone),

g) Cortical bone chips (allograft bone),

h) Demineralized Bone Matrix chips or powder,

i) Growth factors such as BMP2, BMP7, and/or

j) Pain medication

According to a non-limiting embodiment, the present invention hasresulted in the development of e.g., MicroFuse® Putty which includes theMicroFuse® Granules.

Having the granules in a phospholipid based carrier would facilitatebetter handling containment of the granules at the site during aprocedure. The superior handling of the product as a result of theaddition of the carrier to the granules has been verified by numeroushandling evaluations.

The superior handling of the present compositions, such as MicroFusePutty, as a result of the addition of the phospholipid carrier hasenabled the following:

1) Superior handling (soft, moldable and dough like) with a certainstickiness and tackiness to it;

2) Ability to mix additional graft materials such as bone/autogenousgraft/blood/BMA/ceramic particles without affecting the handling of theproduct;

3) Use of the product in posterolateral spinal fusion, as packing insideinterbody cages and as a bone void filler (during surgery in bonegrafting) in extremities, long bones, and CMF pelvis; and

4) Ability to use the composition for delivering BMPs/other growthfactors or for drug delivery. This composition may also help in thecontainment/confinement of growth factors like BMP2 within an interbodycage which has a significant clinical benefit.

The present compositions may be administered to a mammal such as a humanfor various uses or applications. For example, the compositions may beadministered as a bone graft substitute in the spine, extremities and/orpelvis. For bone grafting, the compositions may be used as bone voidfiller. The handling characteristics of example compositions haveenabled it to be used e.g., in posterolateral spinal fusion, packinginside interbody cages, and as a bone void filler in extremities/longbones and pelvis devices, and CMF (Craniomaxillofacial) devices. Thecompositions may be used for drug delivery or for delivery of growthfactors (such as PDGF, BMP, etc.). The carriers may also be used as ahemostatic agent (stops blood flow).

Implants

Other example embodiments include for example, one or more implantdevices that may include a device for implantation into a mammal, suchas a human, and the present composition on or in the device. Thecomposition may additionally include any component that may be desirablefor implantation or delivery with the device, such as bone graftmaterials and/or active ingredients.

The present devices may be used for various purposes e.g.,posterolateral spinal fusion devices or interbody cages or other devicesbeing implanted to a mammal for any number of reasons. The presentcompositions may be coated on or included in an implant device. Thus,the present invention further encompasses such devices having one ormore of the present compositions thereon or therein.

Method of Making Compositions and Preparing Compositions for Delivery

Non-limiting example embodiments herein include methods of making thepresent carrier compositions for implantation into a mammal. In thepresent methods of preparing compositions for delivery to a mammal, onemay start out e.g., with granules (e.g., MicroFuse Granules), powder orparticulates; or with a composition (e.g., MicroFuse Putty) that maycontain one or more of granules, powder and particulates; and add bloodor bone marrow aspirate (BMA) thereto. BMA is essentially blood exceptthat it has more of the cells that are needed for bone regeneration.

By way of example of combining blood or BMA with granules, powder orparticulates, FIG. 4 shows the addition of the BMA to MicroFuse Granules(FIG. 1) directly. Because the Granules are all porous they wick in theblood.

As indicated above, further examples include adding blood or BMA with acomposition that includes polymer, phospholipid and at least one ofgranules, powder or particulates. The methods may include mixing thepresent compositions with at least one component selected from the groupconsisting of one or more graft materials and one or more activeingredients.

Thus, non-limiting example embodiments herein include methods of makingthe present compositions, which may include for example, preparing amixture of polymer and phospholipid to make a carrier. The methods mayfurther include mixing one or more granules, powders, particulates,graft materials and/or active ingredient with the carrier. By way ofnon-limiting example, an embodiment of the present composition mayinclude mixing together polymer granules (e.g. MicroFuse® ST granules),pluronic F127 and Phosal 50 PG to make a MicroFuse putty composition.According to example embodiments, the carrier may be first prepared andone or more granules, powders and/or particulates or other ingredientsmixed therewith. The ingredients may be mixed however in another orderor simultaneously.

By way of example, the present methods may include providing a carriercomposition (which includes the polymer and phospholipid components andoptional additional components, such as MicroFuse granules) in a bowland mixing blood or bone marrow aspirate (BMA) into the composition. Byway of non-limiting example, the mixing may take place using a glovedhand. According to example embodiments, bone may also be added to thecomposition and mixing of the ingredients (MicroFuse putty,blood/marrow, and bone) can be performed using fingers (gloved hand). Inthese examples, because the pores of the granules are filled with thecarrier material the granules in the putty don't wick in the BMA. Thehandling of these final formulations is excellent even in the presenceof blood/BMA and bone (Carrier/Granules), (Carrier/Powder), (CarrierParticulates).

Other non-limiting example embodiments herein include methods of makingthe present compositions, which may include for example, mixing polymergranules (e.g. MicroFuse® ST granules) for example, in a syringe, withthe phospholipid carrier that includes Pluronic F127 and Phosal 50 PG tomake a putty composition.

For example, as shown in FIG. 3, biodegradable polymer granules, such asthe MicroFuse® Granules depicted in FIG. 1, may be combined with abioresorbable phospholipid-based carrier, which includes for example,Pluronic F127 and Phosal 50 PG, as depicted in FIG. 2, to form novelcarrier compositions according to the present invention. Although inFIG. 3 the composition (entitled “MicroFuse Putty” in the figure) iswithin a syringe-like delivery device, it should be understood that thecompositions may be administered in any number of ways to a subject, forexample within or on an implant device that will be implanted into themammal. Additionally, although FIG. 3 depicts the use of particulargranules (i.e., MicroFuse granules), it is contemplated that otherbiodegradable polymer granules may be substituted therefore and formedinto the present compositions in accordance with the present invention.

The present invention further encompasses methods of making compositionsfor implantation into a mammal, which include mixing at least one of thepresent compositions with at least one component selected from the groupconsisting of one or more graft materials and one or more activeingredients. The bone graft materials may include for exemplary graftmaterial discussed herein or otherwise known to those skilled in theart, including, but not limited to bone, autogenous graft, blood, BMP,growth factors, and ceramic particles.

Further included are methods as depicted for example, in FIG. 7, whichinclude heating a polymer to form a melted polymer, combining aphospholipid with the melted polymer, adding at least one additioncomponent selected from granules, powder and particulates, and kneadingthe polymer, phospholipid and at least one additional component until amixture of the polymer, phospholipid and at least one additionalcomponent hay a temperature of about 38-48° or about 43° C.

Methods of Treating Mammals

Also provided are methods of treating mammals, such as humans, byadministering to a mammal at least one of the present compositions.Additional methods of treatment may include for veterinary applications.Those skilled in the art would be able to ascertain, which mammals maybe treated by the various methods. According to non-limiting exampleembodiments the at least one additional component selected from thegroup consisting of one or more graft materials and one or more activeingredients may also be administered either as part of the composition,or in addition thereto. According to non-limiting example embodiments,the present compositions may be directly administered to a mammal orthey may be administered either on or in an implant that is insertedinto a mammal, e.g., during a surgical procedure. According to exampleembodiments the one or more graft materials and/or one or more activeingredients may be administered (e.g. included in the composition) in aneffective amount for achieving an intended purpose of the graftmaterials and/or active ingredient in the mammal being treated. Aneffective amount may be determined by one skilled in the art such as aphysician. Non-limiting examples of additional ingredients or activeingredients that may be administered in accordance with the presentinvention may include e.g., ingredients for drug delivery (e.g., withloaded microspheres), pain medication, and/or delivering growth factors(PDGF, BMP etc.)

According to non-limiting example embodiments, the present compositionsmay be administered to a mammal by themselves, or alternatively in or onan implant that is inserted into a mammal.

Such methods may further include administering one or more graftmaterials and/or one or more active ingredients, either as part of thepresent compositions or along therewith.

Kits

Other example embodiments are directed to kits that include the presentcompositions or one or more ingredients thereof, and may further includee.g., instructions for making and/or using the compositions; one or moreimplant devices into or onto which the composition may be incorporated;granules, powders or particles, tools or devices for mixing and/orstoring the compositions; tools or devices for inserting the presentcompositions or implant devices into a mammal; one or more graftmaterials and/or active ingredients that may be provided with or carriedby the present compositions; and/or any other components or devices thatmay be useful in making and/or using the present compositions or implantdevices.

Kits provided herein may include for example, one or more polymers suchas pluronic or PEG polymers, and one or more phospholipids, such as aPhosal. By way of example, kits may include Pluronic F127 and Phosal 50PG, and optionally one or more of the additional ingredients discussedherein, such as granules, powders and/or particles. By way of example,kits provided herein may include Microfuse Granules; Pluronic F127, andPhosal 50 PG.

The following examples are provided to further illustrate variousnon-limiting embodiments and techniques encompassed by the presentinvention. It should be understood, however, that these examples aremeant to be illustrative and do not limit the scope of the claims. Aswould be apparent to skilled artisans, many variations and modificationsare intended to be encompassed within the spirit and scope of thepresent disclosure.

EXAMPLES Example 1

Compositions according to the present invention may be prepared e.g., inany of the following different sizes (which are similarly sizes in whichloose polymer granules may be available): 2.5 cc, 5 cc, 10 cc and 20 cc(e.g. in syringes). It should be understood that other size preparationsmay be made as well. The following table sets forth various non-limitingexample embodiments of compositions in the indicated volumes:

MicroFuse Putty Composition by Weight MicroFuse ST Pluronic PhosalGranules F127 50PG Weight 38% 40% 22% Volume (gm) (by weight) (byweight) (by weight) 2.5 cc  2.75 1.05 1.10 0.60  5 cc 5.5 2.10 2.20 1.2010 cc 11 4.20 4.40 2.40

In each of the above formulations, polymer granules (i.e., MicroFuse®granules) are mixed with indicated amounts of Pluronic F127 and Phosal50.

Example 2

In this example, a method for preparing a carrier composition accordingto the present embodiments is described.

FIG. 6 depicts example raw materials that may be used in exampleembodiments of the carrier composition of the present application. Themethod of making the present example carrier and the order of steps areas follows:

Step 1

The polymer is heated at 140° C. for 2 hrs to completely melt thepolymer.

Step 2

After the polymer is melted, a phospholipid e.g., Phosal 50PG is addedto the polymer (for example in a mixing bowl) and mixing is carried oute.g., on a Hamilton Beach Mixer. The temperature of the batch ismeasured using a temperature data logger with the thermocouple placed onthe bowl on the outside. Initially, the mix appears golden yellow and isentirely a liquid. Over time, as the temperature of the batch falls downand the mix appears to have a cake mix like consistency. As this isprogressively going on, the polymer (in this example, Pluronic F127,)cools down below its melt point causing the mix to turn lemon yellow.This takes about 15-20 minutes depending on the size of the batch.

Step 3

When the temperature on the batch falls down to 39° C. (measured on theoutside), Granules are added to the Carrier Mix and the mixing iscontinued for about 1 min. The temperature on the inside is going to behigher and hence the granules can only be added once the temperature setpoint of 39° C. has been attained.

Step 4

The consistency of the Granule/Carrier mix changes to a thick viscousstate after approximately 1 minute of mixing. The whole batch is thenscooped out and the kneading of the Granule/Carrier batch is carried oute.g., on the Electrolux Assistent Mixer until the temperature of thebatch falls down to about 41° C-45° C. or about 43° C. If theGranule/Carrier mix is not kneaded until it cools down, it changes to asolid waxy state. This is a very important phenomenon which was observedduring development. The kneading of the granule/carrier mix resulted ina soft doughy putty whereas cooling of the batch without kneadingresulted in a rigid waxy end product. This may be explained by the factthat the addition of the soybean oil (Phosal 50PG) probably results inthe introduction of the lipid molecules within the amorphous polymer(Pluronic F127) network which prevents the melted polymer from revertingback to a rigid solid state.

Although the invention has been described in example embodiments, thoseskilled in the art will appreciate that various modifications may bemade without departing from the spirit and scope of the invention, andsuch modifications are therefore included herein. It is therefore to beunderstood that the inventions herein may be practiced other than asspecifically described. Thus, the present embodiments should beconsidered in all respects as illustrative and not restrictive.Accordingly, it is intended that such changes and modifications fallwithin the scope of the present invention as defined by the claimsappended hereto.

What is claimed is:
 1. A method of preparing a carrier compositioncomprising: heating a polymer to form a melted polymer, combining aphospholipid with the melted polymer to form a mixture of the polymerand phospholipid; adding one or more graft materials comprisingsynthetic bone graft substitute (BGS) to the mixture; adding one or moreactive ingredients to the mixture, the one or more active ingredientsselected from the group consisting of ceramic beads, particulates,granules, calcium phosphate particles, hydroxyapatite particles,silicated hydroxyapatite particles, bioactive glass particles,cancellous chips, cortical bone chips, and demineralized bone matrixchips; and kneading the polymer, phospholipid, synthetic bone graftsubstitute, and one or more active ingredients until a mixture of thepolymer, the phospholipid, synthetic bone graft substitute, and the oneor more active ingredients is about 38-48° C. to form the carriercomposition.
 2. The method of claim 1, wherein the polymer is present inan amount of about 22-70% by weight.
 3. The method of claim 1, whereinthe polymer comprises at least one poloxamer.
 4. The method of claim 1,wherein the polymer comprises polyethylene glycol.
 5. The method ofclaim 1, wherein the polymer has a melting point of about 60 ° C.
 6. Themethod of claim 1, wherein the phospholipid is present in an amount ofabout 17-65% by weight.
 7. The method of claim 1, wherein thephospholipid comprises a soybean derived phospholipid.
 8. The method ofclaim 1, wherein the carrier composition is in the form of a putty, adough, or a paste.
 9. The method of claim 1, wherein the carriercomposition is packaged in a 2.5 cc, 5 cc, 10 cc, or 20 cc syringe. 10.A method of treating a mammal by administering to a mammal at least onecarrier composition prepared according to claim
 1. 11. A method oftreating a mammal by administering to the mammal an implant device forplacement in a mammal, said implant device comprising the compositionprepared according to claim 1 thereon or therein.
 12. A method ofpreparing a carrier composition comprising: heating a polymer to form amelted polymer, combining a phospholipid with the melted polymer; addingone or more graft materials comprising synthetic bone graft substitute(BGS); and cooling the polymer, phospholipid, and synthetic bone graftsubstitute until a mixture of the polymer, the phospholipid, and thesynthetic bone graft substitute is about 38-48° C.
 13. The method ofclaim 12, wherein the polymer is present in an amount of about 22-70 %by weight.
 14. The method of claim 12, wherein the polymer comprises atleast one poloxamer.
 15. The method of claim 12, wherein the polymercomprises polyethylene glycol.
 16. The method of claim 12, wherein thepolymer has a melting point of about 60° C.
 17. The method of claim 12,wherein the phospholipid is present in an amount of about 17 -65 % byweight.
 18. The method of claim 12, wherein the phospholipid comprises asoybean derived phospholipid.
 19. The method of claim 12, wherein thecarrier composition is in the form of a putty, a dough, or a paste.